Is CAD p.Met985fs (c.2953_2954del) pathogenic?

CAD p.Met985fs (c.29532954del) is classified Pathogenic in CAD (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.0011%, sas); Associated with developmental and epileptic encephalopathy, 50.

What condition is associated with CAD p.Met985fs (c.2953_2954del)?

CAD p.Met985fs (c.2953_2954del) is associated with developmental and epileptic encephalopathy, 50 (ClinVar).

How common is CAD p.Met985fs (c.2953_2954del) in the general population?

CAD p.Met985fs (c.2953_2954del) is very rare (popmax 0.0011%, sas) (gnomAD).

How is CAD-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CAD p.Met985fs

c.2953_2954del · VCV3382954

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

developmental and epileptic encephalopathy, 50

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 19 of 44
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.39	GERP 0.4, phastCons 0.99

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,054 alleles

Overall 0.000137% 2/1,460,486 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,054
European (non-Finnish)	8.48e-05%	1,178,768

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CAD
Protein: p.Met985fs
Coding: c.2953_2954del
MANE Select: NM_004341
Type: Deletion
Location: chr2:27233102 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 985: the 'cpsase b' region; the 'cpsase (carbamoyl phosphate synthase)' region

Full CAD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 50 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CAD-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CAD p.Ile945fs Likely pathogenic ★ same condition
CAD p.Leu1728fs Likely pathogenic ★ same condition
CAD p.Phe1849fs Pathogenic ★ same condition
CAD p.Val1241fs Likely pathogenic ★ same condition
CAD p.Glu2208fs Uncertain significance ★ same condition
CAD p.Met985Lys Uncertain significance ★ ⚠ same residue
CAD p.Arg1789Ter Pathogenic ★★ same condition
CAD p.Arg1810Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cad-p-met985fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown